Association of γ-Secretase with Lipid Rafts in Post-Golgi and Endosome Membranes
Open accessAbstract
Alzheimer's disease-associated beta-amyloid peptides (Abeta) are generated by the sequential proteolytic processing of amyloid precursor protein (APP) by beta- and gamma-secretases. There is growing evidence that cholesterol- and sphingolipid-rich membrane microdomains are involved in regulating trafficking and processing of APP. BACE1, the major beta-secretase in neurons is a palmitoylated transmembrane protein that resides in lipid rafts. A subset of APP is subject to amyloidogenic processing by BACE1 in lipid rafts, and this process depends on the integrity of lipid rafts. Here we describe the association of all four components of the gamma-secretase complex, namely presenilin 1 (PS1)-derived fragments, mature nicastrin, APH-1, and PEN-2, with cholesterol-rich detergent insoluble membrane (DIM) domains of non-neuronal cells and neurons that fulfill the criteria of lipid rafts. In PS1(-/-)/PS2(-/-) and NCT(-/-) fibroblasts, gamma-secretase components that still remain fail to become detergent-resistant, suggesting that raft association requires gamma-secretase complex assembly. Biochemical evidence shows that subunits of the gamma-secretase complex and three TGN/endosome-resident SNAREs cofractionate in sucrose density gradients, and show similar solubility or insolubility characteristics in distinct non-ionic and zwitterionic detergents, indicative of their co-residence in membrane microdomains with similar protein-lipid composition. This notion is confirmed using magnetic immunoisolation of PS1- or syntaxin 6-positive membrane patches from a mixture of membranes with similar buoyant densities following Lubrol WX extraction or sonication, and gradient centrifugation. These findings are consistent with the localization of gamma-secretase in lipid raft microdomains of post-Golgi and endosomes, organelles previously implicated in amyloidogenic processing of APP.
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In N2a cells, γ-secretase co-localizes in TGN vesicles with syntaxin 6 and VAMP4 and in late endosomal membranes labeled with syntaxin 13.
“In N2a cells, γ-secretase co-localizes in TGN vesicles with the markers syntaxin 6 and VAMP4 and in the late endosomal membranes, labeled with syntaxin 13 [68].”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [68]
The subcellular-localization and immunoisolation results show that γ-secretase components in N2a cells share membrane fractions or raft patches with syntaxin 6, VAMP4, and syntaxin 13. Although the Fig. 6 description labels syntaxin 13 a late-endosome marker, the results text describes it as an early- and recycling-endosome protein; the experiments do not establish colocalization specifically in late endosomal membranes. Page numbers are unavailable in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe endogenous mature γ-secretase is situated in the TGN and/or the endosomal pathway.
“Different studies have analyzed the location of the endogenous mature γ-secretase, concluding that it is situated in the TGN and/or the endosomal pathway.”
From Sorting nexin 17 regulates ApoER2 recycling and reelin signaling (2014) · cites this paper as [68]
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- Authors
- Vetrivel, K. S., Cheng, H., Lin, W., Sakurai, T., Li, T., Nukina, N., Wong, P. C., Xu, H., & Thinakaran, G.
- Affiliations
- University of Chicago (US)
- RIKEN Center for Brain Science (JP)
- Johns Hopkins University (US)
- Sanford Burnham Prebys Medical Discovery Institute (US)
- Corresponding author
- Thinakaran, Gopal
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-10
- Volume
- 279
- Issue
- 43
- Pages
- 44945-44954
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC1201506
- OpenAlex
- W2003890494
- Cited by
- 413
- References
- 3
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 5 · 2023: 7 · 2022: 10 · 2021: 9 · 2020: 12 · 2019: 11 · 2018: 12 · 2017: 12 · 2016: 20 · 2015: 16 · 2014: 24 · 2013: 21 · 2012: 31
- FWCI
- 18.93
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Alzheimer's Association
- American Health Assistance Foundation
- Illinois Department of Public Health
- National Institutes of Health
- National Institute on Aging (R01AG019070, AG 19070, R01AG021495, AG21495)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
- Keywords
- gamma-secretase, lipid rafts, amyloid precursor protein, amyloid-beta, BACE1, presenilin 1, nicastrin, APH-1, Pen-2, endosomes, SNARE proteins, syntaxin 6, cholesterol, sphingolipids, amyloidogenic processing, Alzheimer's disease
- MeSH terms
- Animals, Biological Transport, Cholesterol, Detergents, Endocytosis, Fibroblasts, Golgi Apparatus, HeLa Cells, Humans, Intracellular Membranes, Lipids, Magnetics, Membrane Glycoproteins, Membrane Proteins, Microscopy, Fluorescence, Mutation, Neurons, Peptide Hydrolases, Endopeptidases, Endosomes, Subcellular Fractions, Sucrose, Aspartic Acid Endopeptidases, Microscopy, Confocal, Transgenes, Membrane Microdomains, Adaptor Proteins, Vesicular Transport, Cell Line, Tumor, R-SNARE Proteins, Qa-SNARE Proteins, Mice, Amyloid Precursor Protein Secretases
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